Summary:[unreadable] The Section on Human Biochemical Genetics studies selected inborn errors of metabolism to provide insight into cellular mechanisms and care for neglected groups of rare disease patients. 1. Members of the Section admitted approximately 55 individuals with cystinosis as inpatients or outpatients to the NIH Clinical Research Center, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, and ophthalmic abnormalities. In addition, they reported striking non-renal complications in 100 adult cystinosis patients, who were examined between 1985 and 2006 and who did not receive substantial oral cysteamine therapy. Long-term oral cysteamine treatment helped prevent the myopathy, retinopathy, diabetes mellitus, swallowing difficulty, and pulmonary dysfunction in cystinosis patients. In collaboration with colleagues in the National Eye Institute, the Section presented the histopathology of the eye in cystinosis, and continues to provide cysteamine eyedrops to patients suffering from photophobia due to corneal cystine crystal accumulation. The collaborative group continues to work to bring cysteamine eyedrops to New Drug Approval by the FDA. The Section serves as the world authority on cystinosis, responding to scores of inquires every year from patients and physicians throughout the world. 2. The Section continues its investigations into alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. In collaboration with the Clinical Centers Rehabilitation Medicine Department, members of the Section have comprehensively described the musculoskeletal manifestations and progression to disability of alkaptonuria patients. The Section has also successfully enrolled 40 alkaptonuria subjects in a randomized clinical trial of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, using hip range of motion as the primary outcome parameter. Interim analysis at 16 months shows promising results. 3. The Section remains the only center in the world investigating both the clinical and basic aspects of Hermansky-Pudlak syndrome (HPS), a rare disorder of oculocutaneous albinism and bleeding due to abnormal formation of intracellular vesicles such as melanosomes and platelet dense bodies. There are 8 genetic subtypes of this disease, and the Section has cared for more than 200 affected individuals. In basic studies, members of the Section and their collaborators reported a normal contingent of alpha granules in HPS platelets, which are known to lack dense granules. They also showed that HPS5 melanocytes display abnormal trafficking of melanogenic proteins. Physicians in the Section have recruited 24 subjects to a randomized, placebo-controlled clinical trial of the antifibrotic agent, pirfenidone, to combat the fatal pulmonary fibrosis of HPS. The outcome parameter is change in forced vital capacity. In an ancillary pilot study, patients with severe, fatal pulmonary fibrosis are treated with a 5-drug regimen in an attempt to arrest their disease. In parallel with these clinical trials, Section physicians are investigating the etiology of the lung fibrosis through studies of cytokine markers in blood and pulmonary lavage fluid. 4. The Section is performing linkage studies of Gray Platelet Syndrome, a disorder in which platelet alpha granules are absent and patients suffer from a bleeding diathesis. In preparation for comparison with Gray Platelet Syndrome, the proteome of normal alpha granules has been characterized and published by members of the group.5. The Section has also initiated studies to identify the gene responsible for White Platelet Syndrome, a macrothrombocytopenia associated with multiple Golgi regions in platelets. 6. An ongoing clinical protocol investigates Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis to define the natural history and determine outcome parameters for future therapeutic intervention. More than 60 patients have been evaluated in this study, and a natural history study of the disorder is being prepared for publication. 7. Fifteen children have been extensively examined under a clinical protocol investigating the premature aging disorder, Hutchinson-Gilford Progeria Syndrome; a manuscript describing the findings has been submitted. 8. Members of the Section continue to investigate Chediak-Higashi disease, a disorder of large intracellular granules and a tendency toward fatal infections. A severely affected infant and a mildly affected adult were compared on clinical, molecular, and cell biological grounds, providing a genotype-phenotype correlation. 9. In collaboration with the Cell Biology of Metabolic Disorders Unit, members of the Section continue to investigate a rare muscle disease, Hereditary Inclusion Body Myopathy (HIBM). The causative gene is GNE, which encodes the bifunctional enzyme UDP-N-acetylglucosamine 2-epimeraseN-acetylmannosamine kinase, responsible for catalyzing the first two steps in sialic acid synthesis. Sialic acid serves as the terminal sugar on glycoproteins that decorate plasma membranes and modulate cell-cell interactions; muscle proteins such as alpha-dystroglycan are heavily sialylated, and the myopathy of HIBM has been attributed to hyposialylation of alpha-dystroglycan and other muscle proteins. In addition to collaborating on HIBM basic research projects and animal model studies with the Unit, the Section has performed a pilot study of intravenous immune globulin G for treating HIBM, based upon the high sialic acid content of immune globulin. In four treated patients, muscle strength and functional activity improved considerably. Physicians in the Section have now submitted a clinical protocol involving provision of the sialic acid precursor, N-acetylmannosamine, to HIBM patients to determine if muscle strength can be restored. The primary outcome parameter is change in quadriceps muscle strength, and implementation of the study awaits FDA approval of an Investigational New Drug exemption for N-acetylmannosamine.